Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12202/3774
Title: Molecular genetics of lymphomagenesis: Transcriptional regulation of a murine retrovirus and chromosomal rearrangements in human non-Hodgkin's lymphomas
Authors: Nieves, Angel
Keywords: Molecular biology.
Genetics.
Oncology.
Issue Date: 1998
Publisher: ProQuest Dissertations & Theses
Citation: Source: Dissertation Abstracts International, Volume: 59-06, Section: B, page: 2591.;Advisors: Jack Lenz.
Abstract: Lymphomagenesis by replication-competent, type-C retroviruses in mice (MuLVs) involves activation of cellular oncogenes by viral transcriptional regulatory sequences that integrate into the cellular genome adjacent to the oncogenes. My research focused on the molecular mechanisms involved in T cell lymphomas induced by the MuLV SL3-3 and in human non-Hodgkin's lymphomas. The main genetic determinant for the pathogenicity of MuLVs is the enhancer within the long terminal repeats (LTRs). The T-cell lymphomagenic MuLV SL3-3 (SL3) contains a c-Myb binding site adjacent to the Ets site. Mutations were introduced into the Ets and c-Myb binding sites. Mutation of the Ets site had little effect on viral pathogenicity. Mutation of the Myb site strongly inhibited pathogenicity.;The c-myc gene is activated by proviral insertion in 15 to 20 percent of T-cell lymphomas induced by MuLVs. Evidence exists that the ability of virus to activate c-myc depends on the nature of the LTR enhancer. Viral LTR enhancer sequences were inserted into a plasmid containing the promoter region of the c-myc gene linked to a reporter gene. Mutation of Myb site almost eliminated enhancer activity in T lymphocytes, while mutation of the Ets site had smaller effects. Thus, the effects of the enhancer mutations on transcriptional activity in T cells paralleled their effects on viral lymphomagenicity.;I have undertaken an analysis of chromosomal rearrangements of chromosome 12 that occur in a fraction of human non-Hodgkin's lymphomas. Chromosomal rearrangements involving chromosome 12q13 are seen in about 15% of non-Hodgkin's B-cell lymphomas. We hypothesized that there was one or more common breakpoints in band 12q13 in these lymphomas. My work was to generate a high resolution physical map of band 12q13 (based on yeast artificial chromosomes (YACs), P1 artificial chromosomes (PACs) and cosmids), and to identify the breakpoints in the lymphomas. We were able to identify a YAC of 940 kilobases (kb) that spanned the breakpoint. A high resolution PAC and cosmid based map was generated for this region, about 1.5 Mb in the center of band 12q13. Two PACs of approximately 120 and 110 kb, respectively, were found to cross the VR breakpoint. Three cosmids were identified that shared a DNA marker with the two PACs. The breakpoint was shown to lie in a stretch of 15 to 18 kbp. The DNA shared marker was an expressed sequence tag (EST) called D12S1237E derived from the 3{dollar}\sp\prime{dollar} untranslated region of an as yet unknown gene. A probe derived from this EST detected a ubiquitously expressed transcript of 9.0 kb by northern analysis of normal tissues. Physical map analysis showed that the transcriptional orientation of this candidate gene is 3{dollar}\sp\prime{dollar} to 5{dollar}\sp\prime,{dollar} centromere to telomere, placing the 5{dollar}\sp\prime{dollar} end of the gene proximal to the breakpoint. Clones were obtained that contained the 3 kb that are located at the 3{dollar}\sp\prime{dollar} end of this transcript. Sequencing of this cDNA failed to detect an open reading frame. (Abstract shortened by UMI.).
URI: https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9838254
https://hdl.handle.net/20.500.12202/3774
Appears in Collections:Albert Einstein College of Medicine: Doctoral Dissertations

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